Understanding how neural circuits are modified by experience is critical for tackling neurodegenerative and psychiatric disorders. The nervous system of Aplysia is an excellent model for studying the cellular and molecular bases of learning and memory, since identified synaptic connections in circuits mediating reflex behaviors undergo bi-directional long-term changes in efficacy that correlate with long-term changes in behavior. Recent work indicates that stimuli that produce long-term facilitation (LTF with repeated applications of 5-HT) recruit and regulate the synthesis, secretion and signaling of a presynaptic neuropeptide called sensorin that results in the activation of multiple signaling pathways required for long-term changes in synaptic efficacy and growth of new synaptic structures. Down regulation of sensorin secretion and its downstream signaling lead to long-term depression (LTD)-like changes including the retraction of neurites and elimination of presynaptic structures. Thus different forms of long-term synaptic plasticity may be produced when the stimuli recruit or regulate the secretion and signaling of a neuropeptide, which in turn regulates the timely and site-specific activation of additional signaling pathways to orchestrate the many cellular and molecular events in both presynaptic and postsynaptic neurons that are needed to initiate and maintain long-term changes at synapses. To explore this hypothesis we will combine cellular (cell culture, electrophysiology, pharmacology, immunostaining and light microscopy) and molecular (RT-PCR, in- situ hybridization, anti-sense or RNAi protein knockdowns) techniques to address the following questions: 1. To determine spatial and temporal sequence of signal pathway activations regulated by 5-HT and sensorin and to determine the respective contributions of each pathway in initiating and maintaining LTF. 2. To determine the role of sensorin and its signaling pathway in activity-dependent LTF. 3. To determine the role of sensorin and its signaling pathway in long-term depression (LTD). The results of these studies will provide important information about how different types of relatively brief stimuli that are sufficient to produce different forms of long-term memory initiate and maintain long-term changes in the properties of specific central synapses activated by the stimuli. [unreadable] [unreadable] [unreadable]